Dispite the decline in the age-specific death rates from coronary artery disease (CAD) since the late 1960's, CAD continues to kill more Amercians than any other disorder, particularly among the elderly. A multifaceted program to define the prevalence, risk factors for, and prognostic significance of silent myocardial ischemia (SI), a marker for significant CAD in apparently healthy individuals has been developed. A. To determine the long term prognostic significance of SI in apparently healthy subjects, we examined the incidence and predictors of future coronary events (CE) over a mean follow-up of 10.9 years,in 407 asymptomatic volunteers aged 40-96 years from the Baltimore Longitudinal Study of Aging (BLSA). By proportional hazards analysis, a concordant positive ECG and thallium response, indicative of SI, was a significant predictor of CE, independent of conventional risk factors. Thus, exercise-induced SI is a potent risk factor for future CE among apparently healthy older adults. B. Although the risk factors contributing to overt coronary artery disease (CAD) have been extensively investigated, very little is known regarding the risk factors for SI in apparently healthy subjects. To address this question we performed tomographic thallium myocardial perfusion scans and assessment of standard CAD risk factors in 281 asymptomatic subjects. By multivariate analysis, older age, male gender, low HDL-cholesterol and elevated waist-hip ratio were associated with exercise-induced SI, as defined in A above. These data may be used to identify an asymptomatic population at high risk for SI, who may benefit from aggressive risk factor modification. C. To examine the importance of Apo E as a genetic marker for the development of early CAD, manifest only by exercise-induced SI, we performed Apo E phenotyping on 172 asymptomatic volunteers ages 46 to 79 who also underwent maximal treadmill exercise testing. The Apo E4 allele was present in 44% of men with ischemic ST segment depression on exercise ECG compared with 17% of men with normal exercise tests, p<.001 despite similar lipid profiles in the 2 groups. Thus, the Apo E allele appears to be a genetic marker for exercise-induced SI and may allow identification of asymptomatic individuals at high risk for developing overt CAD.